1. Field of the Invention
The present invention relates to a calcitonin pharmaceutical composition having improved stability. More specifically, it relates to a solid calcitonin pharmaceutical composition having improved stability which includes calcitonins and ethylene diamine tetraacetates.
2. Description of the Related Art
Calcitonins are calcium regulating hormones secreted from the thyroid glands of mammals or the lateral thyroid glands of nonmammals. In chemical structure they correspond to single polypeptides including 32 amino acid residues. However, the arrangements of the amino acids differ among types of animals. In particular, there is a clear difference between mammalian calcitonins (mainly human calcitonin and swine calcitonin) and nonmammalian calcitonins (mainly salmon calcitonin and eel calcitonin).
In addition to these natural types of calcitonins, as nonnatural types, large numbers of derivatives and analogs are synthesized by removing, replacing, reversing, or otherwise treating one or more of the amino acid groups or arrays of natural calcitonins or by adding an N terminal group or C terminal group. Further, calcitonin gene related peptides are hormones existing in the brain, heart, etc. of mammals and are comprised of 39 amino acids with the 2nd position and seventh position cysteines bonded by S--S bonds.
These natural calcitonins and nonnatural calcitonins are referred to all together as calcitonins.
The action of these calcitcnins is to reverse the effects of parathyroid hormones on the bones and kidneys. They have the action of inhibiting bone resorption and reducing blood calcium and the action of reducing blood serum phosphates. Therefore, animal calcitonin has been administered for the treatment of tumors, hyperparathyroidism, and grave hypercalcemia accompanying vitamin D poisoning. Further, they are suitable for treatment of infant cataplectic hypercalcemia, osteoporosis, Sudeck's atrophy, and Paget's disease. Further, calcitonin gene related peptides block the outflow of calcium stored in the cells from the cells. On the other hand, they do not block the inflow of calcium existing in the fluid outside the cells into the cells. In the coronary arteries, this mechanism eases the constriction of the muscles in the veins and reduces blood pressure. As a result of this action, usefulness is expected for the treatment of ischemic diseases of the brain or heart and high blood pressure or for the treatment of central nervous system diseases due to action as a neurotransmitter.
These useful calcitonins are supplied to the medical field as various preparations, but calcitonins are chemically unstable in the same general way as peptides, so there has been a desire for stabilized preparations with guaranteed potency.
In the past, as methods for stabilization of calcitonins, there have been known the method of freeze drying calcitonins and human albumin (Japanese Unexamined Patent Publication (Kokai) No. 63-5028) and the method of dispersion of calcitonins in gelatin and/or hydroxypropylmethylcellulose (Japanese Unexamined Patent Publication (Kokai) No. 61-282320).
On the other hand, contamination by microorganisms has become a problem in aqueous preparations containing calcitonins. To prevent this, there is known the method of adding benzalkonium chloride as a preservative (Japanese Unexamined Patent Publication (Kokai) No. 59-89619).
Furthermore, Japanese Unexamined Patent Publication (Kokai) No. 59-130820 discloses a liquid composition comprising a surfactant and calcitonin. This reference further discloses the optional use of disodium ethylenediamine tetraacetate as a preservative. However, this reference does not teach the advantageous effects of ethylenediamine tetraacetates for stabilizing calcitonins in a solid composition. Especially, the advantage effects obtained by the use of the ethylenediamine tetraacetates among the other preservatives are not taught in this reference.
While the stability of preparations of calcitonins stabilized by the above-mentioned methods is improved compared with the stability prior to the stabilization, it is still insufficient and the preparations must be refrigerated for storage. Therefore, there has been a desire for preparations of calcitonins having more improved stability.
Further, even among calcitonins, there are some nonnatural types of calcitonins (for example, elcatonin) preparations made by chemically modifying parts of natural types of calcitonins to improve their stability which are improved in stability over preparations of natural types of calcitonin and can be stored at room temperature, but the stability cannot be said to be sufficient and there is a danger of reduction in activity when exposed to stringent conditions in distribution. Therefore, there has been a demand for preparations made even more stable in all types of calcitonins, both natural and nonnatural.